Constitutive increase in active GLP-1 levels by the DPP4 inhibitor ASP4000 on a new meal tolerance test in Zucker fatty rats

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is essential for the regulation of insulin secretion and glucose homeostasis. GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP4); therefore, DPP4 inhibitors are considered to be a novel class of oral antihyperglycemic agents. These agents are currently under development as treatments for type 2 diabetes. Normally, oral glucose tolerance tests are used for evalating glucose-lowering efficacy, but the augmentation of active GLP-1 via DPP4 inhibition in this test was transient. It has been proposed that the secretion of GLP-1 is regulated by the rate of entry of nutrients into the small intestine; therefore, we have established the new meal tolerance test method using solid diet. This model allows for the continuous monitoring of active GLP-1 secretion after food intake. ASP4000 is an orally effective inhibitor of DPP4 that greatly augments meal-stimulated circulating levels of active GLP-1 constitutively and improves hyperglycemia. Acarbose improved glucose tolerance in the test to a degree similar to that of the DPP4 inhibitor. Our new meal tolerance test is useful for evaluating postprandial hyperglycemia and could be an excellent model for studying the secretion of active GLP-1 via the inhibition of DPP4.